WO2005095355A1 - Process for producing n,n'-carbonyldiimidazole - Google Patents

Abstract

A process for producing N,N'-carbonyldiimidazole by reacting phosgene, diphosgene, or triphosgene with imidazole in an inert solvent, characterized in that a gaseous or liquid basic compound represented by the following general formula (1) is added in an inert solvent to the imidazole hydrochloride yielded as a by-product of that reaction to conduct neutralization reaction and the imidazole thus generated is circulated and used as a starting material for N,N'-carbonyldiimidazole production. In the general formula (1), R1, R2, and R3 each independently represents hydrogen, methyl, or ethyl. The CDI produced by the process is a compound useful in the fields of medicine synthesis, agrichemical synthesis, peptide synthesis, etc. for intermolecular condensation reactions, intramolecular condensation reactions for synthesizing, e.g., N-carboxy anhydrides, production of activated esters, etc. It is especially suitable for use in applications where colorlessness is required.

Description

 Specification

 Process for producing Ν, Ν'-carbonyldiimidazole

 Technical field

 The present invention relates to a method for producing Ν, N′-carbonyldiimidazole. More specifically, according to a method for producing Ν, N′-carbonyldiimidazole by reacting imidazole with phosgene or a polymer thereof in an inert solvent, imidazole hydrochloride by-produced and a basic conjugate are produced. The present invention relates to a process for circulating and using imidazole produced by a neutralization reaction with a gas or liquid as a raw material for producing Ν, N'-carbonyldiimidazole. Background art

 [0002] Ν, N'-carbodiimidazole (hereinafter abbreviated as CDI) is used for pharmaceutical synthesis such as condensation reaction between molecules, intramolecular condensation reaction such as synthesis of カ ル ボ ン -carboxylic acid anhydride, and formation of activated ester. It is a valuable compound used in fields such as biochemical synthesis, agricultural chemical synthesis, and peptide synthesis. The most common method of synthesizing CDI is to react imidazole with phosgene in an inert solvent designed by H. A. Staab. In this method, as shown in the following chemical formula, half of the imidazole is used as a scavenger for hydrogen chloride formed during the reaction, and is separated and removed from CDI after the reaction is completed.

 [0003] [Formula 1]

[0004] For the purpose of utilizing imidazole in a total reaction, there has been disclosed a method of using an organic base as a scavenger for generated hydrochloric acid (for example, Patent Documents 1 and 2). Further, a method has been practiced in which imidazole is silylated with a silylating agent such as trimethylsilyl chloride so that hydrochloric acid is not generated. However, when an organic base is used, impurities are generated as soon as the organic base is not completely inert to phosgene and remain in the product CDI, which causes a decrease in purity. In the case of imidazole silylidani, the ability to suppress the generation of hydrochloric acid and to circulate and use the silylating agent is generally stable. Requires an accompanying capital investment for special handling for not silylating agents. These methods described above are difficult to use as industrial processes for obtaining inexpensive and high-purity CDI.

 [0005] Therefore, a method has been used in which imidazole hydrochloride by-produced is neutralized with an inorganic base such as sodium hydroxide or an aqueous solution thereof, and the imidazole is recovered and returned as a raw material for CDI production (for example, see Patent Reference 3, patent reference 4). However, even in this method, if imidazole is recovered using water as a solvent, imidazole is water-soluble, so that labor and cost due to extraction with an organic solvent that does not mix with water are expended. It becomes. Furthermore, even if recovery is performed using an organic solvent, CDI is extremely hydrolyzable, so it is necessary to add a step to remove water generated during the neutralization reaction.

 [0006] Patent Document 1: International Publication No. 98Z31672 pamphlet

 Patent Document 2: International Publication No. 00Z02863 pamphlet

 Patent Document 3: International Publication No. 00Z14072 pamphlet

 Patent Document 4: International Publication No.OOZ06551 pamphlet

 Disclosure of the invention

 Problems to be solved by the invention

[0007] As described above, removal of hydrogen chloride by-produced during the reaction in the industrial production process of CDI is a major problem, and when imidazole is used as a raw material and as a scavenger for hydrogen chloride, imidazole hydrochloride is used. It is desired to develop a method for easily recovering and reusing imidazole without generating water. In addition, the manufactured CDI is always required to have less coloring, and a manufacturing method that does not require a special process for removing coloring is also required.

[0008] The present inventors have conducted intensive studies to solve this problem. As a result, imidazole hydrochloride by-produced during the reaction is dissolved or dispersed in an organic solvent, the imidazole hydrochloride is neutralized with a gas or liquid of a basic compound, and the neutralized product is removed. Can be easily circulated as a raw material for CDI production and completed the present invention. That is, the present invention produces N, N'-carbodiimidazole by reacting phosgene, diphosgene or triphosgene with imidazole in an inert solvent, and converts the imidazole hydrochloride by-produced at that time into an inert solvent. In which a gas or a liquid of the basic conjugate represented by the general formula (1) is added to carry out a neutralization reaction, and the resulting imidazole is used as a reaction raw material for producing N, N'-carbonyldiimidazole. A method for producing N, N, 1-carbodiimidazole, wherein the method is used in circulation.

[Formula 2]

R ¹

 (1)

R ² \ R ³ R ³ each independently represents a hydrogen atom, a methyl group or an ethyl group.

 The present invention also relates to each of the following. That is, the above-mentioned method for producing N, N, 1-carbodiimidazole wherein the basic compound represented by the general formula (1) is gaseous ammonia or liquid ammonia;

 Wherein the inert solvent is one or a mixture of two or more selected from the group consisting of chain ethers, cyclic ethers, and chain ester esters. The method for producing N, N, 1-carbodiimidazole as described above , A process for producing N, N'-carbodiimidazole as described above, which is tetrahydrofuran;

 Imidazole produced by the neutralization reaction of by-product imidazole hydrochloride with the basic compound represented by the general formula (1) is taken out as a solid by crystallization or removal of the solvent, and is used for the production of N, N'-carbonyldiimidazole. A method for producing the above-mentioned N, N'-force rubonyldiimidazole, which is circulated and used as a raw material for

The imidazole produced by the neutralization reaction between the by-product imidazole hydrochloride and the basic compound represented by the general formula (1) is converted into an inert solvent solution or a dispersion slurry of the inert solvent. A process for producing N, N'-carbonyldiimidazole as described above, which is circulated and used as a raw material for producing N, N'-carbodiimidazole without adding a water removing step; The neutralization reaction with the basic compound represented by the formula (1) is carried out in an inert solvent, the hydrochloride of the basic compound is removed by filtration, and the imidazole formed is directly treated with the inert compound. The above-mentioned N, N'-carbo which is circulated and used as a raw material for the production of N, N'-carboldiimidazole without adding a water removing step as a solvent solution or a slurry of the inert solvent. -A process for producing rudiimidazole; and

 The imidazole formed by the neutralization reaction between the by-product imidazole hydrochloride and the basic compound represented by the general formula (1) and imidazole newly supplied are mixed in an arbitrary ratio, and N, N, and carboxy are mixed. -The process for producing N, N'-carbo-ludiimidazole used as a raw material for producing rudiimidazole.

 [0010] In the present invention, imidazole hydrochloride is neutralized by an organic base and neutralized without generation of water as occurs when neutralizing with an inorganic base. Further, the basic conjugate represented by the general formula (1) is inexpensive and easy to handle. Furthermore, the basic compound represented by the general formula (1) has a low boiling point, and even if the basic compound represented by the general formula (1) remains in the system after completion of the neutralization reaction, boiling or Since it can be easily removed by publishing with an inert gas, there is no adverse effect due to the residual basic conjugate during CDI synthesis by recycle use of imidazole.

[0011] The hydrochloride of the basic compound represented by the general formula (1) generated during the neutralization reaction is removed by filtration. The imidazole that has been neutralized to a free state can be recycled in the form of a solution or as a solid after distilling off the solvent and used as a raw material for CDI production without adding a water removal step. it can. When the solution is used in a circulating state, the imidazole formed is used as a solution of an inert solvent or a dispersion slurry of the inert solvent. In this case, the neutralization reaction between the by-product imidazole hydrochloride and the basic conjugate represented by the general formula (1) is performed in an inert solvent, and the hydrochloric acid of the basic conjugate is treated with hydrochloric acid. The salt may be removed by filtration, and the resulting imidazole may be circulated and used as it is as a solution of the inert solvent or a dispersion slurry of the inert solvent. [0012] Phosgene, diphosgene or triphosgene is reacted with imidazole to produce N, N'-force liponyldiimidazole. As a solvent used, phosgene or by-produced hydrogen chloride does not react. As long as it is an active solvent, deviation can also be used. Also, even when the solvent has some reactivity, such a solvent can be used because the reaction between imidazole and phosgene and the reaction between imidazole and hydrogen chloride are preferred.

 [0013] In consideration of removing a trace amount of colored impurities generated during the reaction, one or a mixture of two or more selected from a chain ether, a cyclic ether, and a chain ester ester is used as the solvent. Is preferred. Even more preferred is tetrahydrofuran. In this case, it is considered that the reason why the trace amount of colored impurities is accurately removed is that chain ethers, cyclic ethers, and chain esters have high solubility in trace amounts of colored impurities. In the present invention, the use of these chain ethers, cyclic ethers, and chain esters as solvents means not only the use of these solvents but also aromatic compounds which have been conventionally used as solvents for CDI production. The present invention also encompasses a method in which a solvent is used by mixing these chain ethers, cyclic ethers, and chain esters. The invention's effect

 According to the production method of the present invention, imidazole hydrochloride by-produced during the production of CDI is neutralized by adding a gas or liquid of a basic compound which is inexpensive and easy to handle! The imidazole can be recovered in a free state without producing water. After that, it became possible to circulate imidazole easily and inexpensively as a raw material for CDI production without adding processes such as extraction and azeotropic dehydration. Further, according to the production method of the present invention, CDI with less coloring can be obtained as compared with the conventional production method.

 BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

 As the imidazole hydrochloride used in the present invention, it is preferable to use imidazole hydrochloride by-produced during the production of CDI in consideration of the purpose of the present invention, but imidazole hydrochloride synthesized separately or other imidazole hydrochloride may be used. Imidazole hydrochloride by-produced during the production of the compound may be used.

[0016] The basic conjugate used in the present invention is particularly limited as long as it is represented by the general formula (1). Not determined. Here, RR ² and R ³ are each independently a hydrogen atom, a methyl group or an ethyl group. As a specific compound, ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, getylamine, triethylamine, methylethylamine, ethyldimethylamine, and among the above-mentioned powers, ammonia is preferably used.

 [0017] The inert solvent is not particularly limited as long as it does not inhibit the reaction between imidazole and phosgenes and the neutralization reaction of imidazole hydrochloride. Specific examples of the inert solvent that can be used in the present invention include cyclic ethers such as tetrahydrofuran and dioxane, chain ethers such as diisopropyl ether and dibutyl ether, and halogenated hydrocarbons such as dichloromethane, chloroform and trichloroethane. Aromatic hydrocarbons such as toluene, xylene, and chlorobenzene, chain esters such as ethyl acetate and butyl acetate, ketones such as acetone and methyl isobutyl ketone, -tolyls such as acetonitrile, and hexane And aliphatic hydrocarbons such as heptane. Preferred are chain ethers, cyclic ethers and chain esters, and particularly preferred is tetrahydrofuran. These organic solvents may be used alone or in combination of two or more.

 In the production method of the present invention, the neutralization reaction of the basic compound with imidazole hydrochloride by gas or liquid is carried out by dissolving or dispersing the imidazole hydrochloride in an inert solvent and introducing the basic compound. It is preferred to do so. Alternatively, there is a method in which imidazole hydrochloride is added to an inert solvent in which a basic compound is dissolved, or an imidazole hydrochloride dissolved or dispersed in an inert solvent is poured. .

 [0019] The basic conjugate used for neutralizing imidazole hydrochloride is used in an amount of 1 to 10 times the molar amount of imidazole hydrochloride. Preference is given to using 1 to 5 moles. The inert solvent used for neutralizing imidazole hydrochloride is used in an amount of 1 to 20 times the weight of imidazole hydrochloride. It is preferable to use 3 to 5 times the weight.

[0020] The neutralization reaction of the basic conjugate of imidazole hydrochloride with a gas or liquid is usually performed at 0 to 100 ° C. It is preferably carried out at 20 to 50 ° C. The reaction time is usually 0.5 to 20 hours. Preferably, it is performed in 2 to 8 hours. The reaction is preferably performed under an inert gas atmosphere such as nitrogen or argon under anhydrous conditions, but the atmosphere conditions are not particularly limited. The reaction solution after completion of the neutralization reaction is preferably filtered under an inert gas atmosphere and under anhydrous conditions in which a neutralized product is filtered at an arbitrary temperature, but the atmosphere conditions are not particularly limited. The recovered filtrate containing imidazole is used as it is or after concentration, as a raw material for CDI production. Further, imidazole is taken out as a solid by an operation such as crystallization and used as a raw material for CDI production.

 [0022] The neutralized and recovered imidazole is dissolved or dispersed in an inert solvent and then subjected to a CDI synthesis reaction by introducing a specified amount of phosgene, diphosgene or triphosgene. At this time, a new imidazole may be added to the neutralized and recovered imidazole, and the unit yield of CDI may be increased to perform the reaction.

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

 Example 1

 [0024] Synthesis of CDI and by-product imidazole hydrochloride using if product imidazole]

 108.3 g (l. 59 mol) of imidazole and 630 g of tetrahydrofuran were added to a 1000 ml flask, and the system was purged with nitrogen and stirred to dissolve imidazole. To this, 39.3 g (0.2 mol) of diphosgene was added dropwise at room temperature over 2 hours. After completion of the dropwise addition, stirring was continued at room temperature for 1 hour, and then the mixture was heated to 55 ° C. and further stirred for 1 hour. The by-product imidazole hydrochloride was filtered by heating and washed with 100 g of tetrahydrofuran. The filtered imidazole hydrochloride was dried under reduced pressure at 40 ° C. to obtain 83.2 g (0.796 mol) of imidazole hydrochloride (recovery rate 100%).

) o

 The filtrate containing CDI was concentrated and crystallized from toluene, and the CDI was filtered off under a nitrogen atmosphere. The filtered CDI was dried under reduced pressure at 40 ° C. to obtain 58.0 g (0.358 mol) of CDI white crystals. (Yield 90%) m.p. 111.2-118.6. C.

 Example 2

 [Neutralization and Recovery of Imidazole by Neutralization Reaction of Imidazole Hydrochloride]

83.0 g (0.794 mol) of the imidazole hydrochloride obtained in [Example 1] and 274 g of tetrahydrofuran were added to a 500-ml flask, and the system was purged with nitrogen, followed by stirring to disperse the imidazole hydrochloride. Ammonia gas is blown at a temperature of 30 to 40 ° C for 4 hours over a period of 251 (1.12 mol). I was crowded. After the introduction of the ammonia gas, stirring was continued at 35 ° C for 1 hour. After the reaction solution was cooled to room temperature, the neutralized product, Shiridani ammonium, was filtered off and washed with 54 g of tetrahydrofuran. The filtrate was concentrated and 150 g of tetrahydrofuran was distilled off to obtain 185.4 g of tetrahydrofuran containing neutralized and recovered imidazole. As a result of gas chromatography and neutralization titration analysis, it was found to contain 48.6 g (0.714 mol) of imidazole. (Recovery 90%) mp 82-88 ° C. Example 3

 [Synthesis of CDI using neutralized and recovered imidazole]

 In a 500 ml flask, 183.4 g of tetrahydrofuran containing 48.lg (0.707 mol) of imidazole obtained in [Example 2] and 140 g of tetrahydrofuran were purged with nitrogen in the power supply system. Thereto, 18.5 g (0.094 mol) of diphosgene was added dropwise at room temperature over 2 hours. Thereafter, the same operation as in [Example 1] was performed to extract CDI white crystals. Yield 24.4 g (0.15 mol) (85% yield) m.p. 111.3-116.9. C.

 Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. is there.

 This application is based on a Japanese patent application filed on March 30, 2004 (Japanese Patent Application No. 2004-099257), the contents of which are incorporated herein by reference.

 Industrial applicability

[0028] CDI produced by the production method of the present invention can be used for pharmaceutical synthesis, agricultural chemical synthesis, peptide synthesis, etc., such as intermolecular condensation reaction, intramolecular condensation reaction such as synthesis of N-carboxylic anhydride, and formation of activated ester. It is a valuable compound used in fields such as synthesis, and is particularly suitable for applications requiring no coloration.

Claims

Claims: N, N'-carbonyldiimidazole is produced by reacting phosgene, diphosgene or triphosgene with imidazole in an inert solvent, and imidazole hydrochloride by-produced at that time is produced in an inert solvent. A gas or liquid of a basic compound represented by the following general formula (1) is added to the mixture to perform a neutralization reaction, and the resulting imidazole is circulated as a reaction raw material for the production of N, N, 1-carbodiimidazole. For producing N, N'-carbonyldiimidazole. [Formula 3] R1 (1)

R ³ each independently represents a hydrogen atom, a methyl group or an ethyl group.  [2] The method for producing N, N'-carbonyldiimidazole according to claim 1, wherein the basic conjugate represented by the general formula (1) is gaseous ammonia or liquid ammonia. [3] The N, N'-carbo according to claim 1 or 2, wherein the inert solvent is one or a mixture of two or more selected from a chain ether, a cyclic ether, and a chain ester. -A method for producing rudiimidazole.  [4] The method for producing N, N, 1-carbodiimidazole according to any one of claims 1 to 3, wherein the inert solvent is tetrahydrofuran. [5] The imidazole produced by the neutralization reaction between the by-product imidazole hydrochloride and the basic compound represented by the general formula (1) is taken out as a solid by crystallization or removal of the solvent, and N, N ′ is obtained. The method for producing N, N'-carbodiimidazole according to any one of claims 1 to 4, which is circulated and used as a raw material for producing carbodiimidazole. [6] The imidazole produced by the neutralization reaction between the by-product imidazole hydrochloride and the basic compound represented by the general formula (1) is converted into an inert solvent solution or an inert solvent dispersion slurry. 6. The method according to claim 1, wherein the N, N'-carbon is used as a raw material for producing N, N'-carbodiimidazole without adding a water removing step. A method for producing carbodiimidazole.  [7] The neutralization reaction between the by-product imidazole hydrochloride and the basic compound represented by the general formula (1) is performed in an inert solvent, and the hydrochloride of the basic conjugate is filtered. And the generated imidazole is circulated as it is as a solution of the inert solvent or as a slurry of the inert solvent without adding a water removal step, as a raw material for producing N, N'-carbonyldiimidazole The method for producing N, N, 1-carbodiimidazole according to any one of claims 1 to 5, wherein the method is used as:  [8] The imidazole produced by the neutralization reaction of the by-product imidazole hydrochloride and the basic compound represented by the general formula (1) is mixed with imidazole newly supplied in an arbitrary ratio. 8. The method for producing N, N, 1-carbodiimidazole according to claim 1, which is used as a raw material for producing N, N'-carbodiimidazole.